Real-World Analyses of the Safety Outcome among a General Population Treated with Statins: An Asian Population-Based Study

Aim: The safety concern of statins is still a major issue for Asians. The aim of this study is to compare the risk of statin-associated adverse events among potent statins. Methods: We included patients from the Taiwan National Health Insurance Research Database who had been treated with atorvastatin, rosuvastatin, or pitavastatin and were without diabetes at baseline. They were classified into three groups: usual-dose statin (atorvastatin 10 mg/d or rosuvastatin 5–10 mg/d), high-dose statin (atorvastatin 20–40 mg/d and rosuvastatin 20 mg/d), and pitavastatin (2–4 mg/d). The primary endpoint is a composite of safety events, including hepatitis, myopathy, and new-onset diabetes mellitus (NODM). We matched age, sex, and year of recruitment among the three groups (n=50,935 in each group) and then used the multivariate Cox proportional hazards model to evaluate the relation between the safety endpoint and different statin groups. Results: After a mean follow-up of 3.08±0.83 years, the safety events occurred in 9.84% in the pitavastatin group, 10.88% in the usual-dose statin group, and 10.49% in high-dose statin group. The multivariate Cox proportional hazards model indicated that usual-dose statin and high-dose statin were associated with a higher risk of the composite safety events compared with pitavastatin (adjusted hazard ratio [aHR]: 1.12, 95% confidence interval [CI]: 1.08–1.17 for usual-dose statin and aHR: 1.06, 95% CI: 1.02–1.10 for high-dose statin). The risks of hepatitis requiring hospitalization and NODM were especially lower in pitavastatin group. Conclusions: Compared with atorvastatin and rosuvastatin, pitavastatin might be associated with a lower risk of safety events in Asians.     

围产期高盐饮食对雄性子代大鼠肠系膜动脉DDAH2/ADMA/eNOS/NO通路的影响

目的探讨围产期高盐饮食对雄性子代大鼠肠系膜动脉二甲基精氨酸二甲胺水解酶2(DDAH2)/非对称性二甲基精氨酸(ADMA)/内皮型一氧化氮合酶(e NOS)/一氧化氮(NO)通路的影响。方法实验大鼠分为2组:正常饮食(NSD)组和高盐饮食(HSD)组,分别在围产期以普通饲料(含1%Na Cl)和高盐饲料(含8%Na Cl)喂养,分娩后雄性子鼠继续相同饲料喂养至16周。测量子鼠血压,检测肠系膜动脉内皮依赖性舒张功能,检测血浆和肠系膜动脉NO含量、e NOS活性、ADMA含量,检测肠系膜动脉DDAH2活性及DDAH1和DDAH2蛋白质表达水平。结果 16周时,HSD组收缩压显著高于NSD组(P0.01)。HSD组大鼠肠系膜血管张力低于NSD组(P0.01);用ADMA孵育血管环后,NSD组血管张力显著减弱,而HSD组未见显著性变化。与NSD组比较,HSD组血浆NO含量降低(P0.05),e NOS活性降低(P0.01),ADMA含量增加(P0.05);HSD组肠系膜动脉NO含量下降(P0.01),e NOS活性下降(P0.01),ADMA含量升高(P0.05)。HSD组DDAH2活性降低(P0.01),DDAH2蛋白质表达显著降低(P0.01);DDAH1蛋白质表达未见显著改变。HSD组肠系膜动脉指标相关性分析:e NOS活性与NO含量呈正相关,ADMA含量与e NOS活性呈负相关,DDAH2活性、DDAH2蛋白质表达与ADMA含量呈负相关。结论母体围产期高盐饮食导致其雄性子代收缩压增高,肠系膜动脉内皮依赖性舒张功能障碍,此与肠系膜动脉DDAH2表达下降、活性降低和DDAH2/ADMA/e NOS/NO通路障碍有关。     

Ankle-arm index is a useful test for clinical practice in outpatients with suspected coronary artery disease.

BACKGROUND: Although a low ankle-arm index (AAI) has been reported to be associated with increased risk of cardiovascular mortality in several populations, no data exist concerning the impact of AAI for outpatients with suspected coronary artery disease (CAD) in the clinical setting. METHODS AND RESULTS: The present study enrolled 840 outpatients (age range 35-87 years, mean age 63.9+/-10.2) with suspected CAD. All patients underwent AAI measurements and coronary angiography, and based on the AAI values, they were divided into group A (AAI <0.9; n=191; CAD positive, 181) and group B (AAI >or=0.9; n=649; CAD positive, 509). Metabolic syndrome (MS), obesity, and level of the inflammatory biomarker high sensitive C-reactive protein (hsCRP) were compared between the 2 groups. The sensitivity, specificity, positive and negative predictive values in predicting CAD with an AAI value <0.9 in all patients were 26.2%, 93.3%, 94.8% and 21.6%, respectively. The patients in group A was significantly older and there was a higher female-to-male ratio than in group B. The presence of hypertension and diabetes mellitus, current smoking status, and levels of low density lipoprotein (LDL)-cholesterol level, uric acid and hsCRP differed significantly between the 2 groups. Group A had a higher percentage of high LDL-cholesterol level, high waist-to-hip ratio and more positive cases of MS than group B. Multivariate logistical regression analysis showed that AAI was related to MS, high levels of hsCRP (>3 mg/L) and uric acid (>7 mg/dl) with odds ratios of 1.769, 3.907 and 2.580, respectively. CONCLUSIONS: The AAI test is an effective tool in predicting CAD in outpatients in clinical practise.     

Local adiponectin treatment reduces atherosclerotic plaque size in rabbits

In this study, we investigated the in vivo role of adiponectin, an adipocytokine, on the development of atherosclerosis in rabbits mainly using adenovirus expressing adiponectin gene (Ad-APN) and intravascular ultrasonography. Serum adiponectin concentrations in rabbits after Ad-APN local transfer to abdominal aortas increased about nine times as much as those before transfer (P < 0.01), about ten times as much as the levels of endogenous adiponectin in adenovirus expressing beta-galactosidase gene (Ad-beta gal) treated rabbits (P < 0.01), and about four times as much as those in the aorta of non-injured rabbits on a normal cholesterol diet (P < 0.01). Ultrasonography revealed a significantly reduced atherosclerotic plaque area in abdominal aortas of rabbits infected through intima with Ad-APN, by 35.2% compared with the area before treatment (P < 0.01), and by 35.8% compared with that in Ad-beta gal-treated rabbits (P < 0.01). In rabbits infected through adventitia, Ad-APN treatment reduced plaque area by 28.9% as compared with the area before treatment (P < 0.01) and 25.6% compared with that in Ad-beta gal-treated rabbits (P < 0.01). Adiponectin significantly suppressed the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1) by 18.5% through intima transfer (P < 0.05) and 26.9% through adventitia transfer (P < 0.01), and intercellular adhesion molecule-1 (ICAM-1) by 40.7% through intima transfer (P < 0.01), and 30.7% through adventitia transfer (P < 0.01). However, adiponectin had no effect on the expression of types I and III collagen. These results suggest that local adiponectin treatment suppresses the development of atherosclerosis in vivo in part by attenuating the expression of VCAM-1 and ICAM-1 in vascular walls.     

Association of Interferon-Gamma Gene Polymorphisms in Taiwanese Children with Biliary Atresia

Background

Biliary atresia (BA) is a devastating neonatal hepatobiliary disease characterized by bile duct inflammation and fibrosis. The pathogenesis remains unclear, but immunologically mediated injury to bile ducts following an infectious insult is likely to play a critical role. Interferon-gamma (IFN-γ) is a key cytokine that affects immune-mediated inflammatory responses.

Objective

This study aims to investigate whether polymorphisms of the IFN-γ (IFNG) gene were associated with susceptibility to BA.

Methods

The IFNG ?1615 C/T, ?183 G/T, +874 A/T, and +2197 A/G polymorphisms were genotyped using the TaqMan assay, and CA repeat microsatellite was analyzed using capillary electrophoresis in 50 children with BA and 788 ethnically matched healthy controls.

Results

The distribution of genotype, allele, and haplotype frequencies of these IFNG gene variants did not differ significantly between children with BA and controls.

Conclusion

Polymorphisms of the IFNG gene do not appear to play a major role in the genetic predisposition to BA in Taiwanese children.     

Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway

The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair-matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (β-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 μM magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5% (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60% (n = 120) of the cases fell into Group 1 (tumor > normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal > tumor, N > T), the LOX expression level in most of the normal tissues examined (80%, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of β-APN (300 μM) and magnolol (25 μM), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of β-APN.